ES2282916T3 - DERIVATIVES OF N- (PHENYL (ALQUILPIPERIDIN-2-IL) METIL) BENZAMIDA, ITS PREPARATION AND ITS APPLICATION IN THERAPEUTICS. - Google Patents

Abstract

CLAIMS 1. Compound that responds to the general formula (I) *** in which: R1 represents either a hydrogen atom, or a linear or branched (C1-C7) alkyl group optionally substituted with one or more atoms of fluorine, either a cycloalkyl (C3-C7) group, or a cycloalkyl (C3-C7) -alkyl (C1-C3) group, or a phenyl-C1-C3 alkyl group optionally substituted with one or two groups methoxy, either a (C2-C4) alkenyl group, or a (C2-C4) alkynyl group; R2 represents either a linear or branched (C1-C7) alkyl or (C3-C7) cycloalkyl group, or a (C3-C7) -cycloalkyl (C1-C3) alkyl group; X represents either a hydrogen atom, or one or more substituents chosen from halogen atoms and trifluoromethyl, linear or branched (C1-C6) alkyl or (C1-C6) alkoxy groups; R3 represents either a hydrogen atom, or one or more substituents chosen from halogen atoms and trifluoromethyl, linear or branched (C1-C6) alkyl, (C3-C7) cycloalkyl, (C1-C6) alkoxy groups, phenyl, cyano, acetyl, benzoyl, thioalkyl (C1-C6), alkyl (C1-C6) sulfonyl, carboxy or alkoxy (C1-C6) carbonyl, or a group of the general formula NR4R5 or SO2NR4R5 or CONR4R5 in which R4 and R5 each represents, independently from each other, a hydrogen atom or a linear or branched (C1-C6) alkyl or cycloalkyl (C3-C7) group, or R4 and R5 form, with the nitrogen atom that carries them, pyrrolidine, piperidine or morpholine cycle; in the state of free base or salt of addition to an acid, hydrate or solvate.

Description

N - [phenyl (aquylpiperidin-2-yl) methyl] benzamide derivatives, their preparation and their application in therapeutics.

The compounds of the invention respond to the general formula (I)

one

in the that:

R1 represents either a hydrogen atom, or a (C 1 -C 7) alkyl group linear or branched optionally substituted with one or more fluorine atoms, or a group cycloalkyl (C 3 -C 7), or a group (C 3 -C 7) cycloalkyl-(C 1 -C 3) alkyl, or a group phenyl (C 1 -C 3) alkyl  optionally substituted with one or two methoxy groups, or a alkenyl group (C2-C4), or a (C 2 -C 4) alkynyl group;

R2 represents either a group linear or branched (C 1 -C 7) alkyl or cycloalkyl (C 3 -C 7), or a group (C 3 -C 7) cycloalkyl-(C 1 -C 3) alkyl;

X represents either a hydrogen atom, or either one or several substituents chosen among the atoms of halogen and trifluoromethyl groups, linear or branched (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy;

R 3 represents either a hydrogen atom, or one or more substituents chosen among the atoms of halogen and trifluoromethyl groups, linear or branched (C 1 -C 6) alkyl, cycloalkyl (C 3 -C 7), (C 1 -C 6) alkoxy, phenyl, cyano, acetyl, benzoyl, thioalkyl (C 1 -C 6), (C 1 -C 6) alkyl sulfonyl, carboxy or (C 1 -C 6) alkoxy carbonyl, or either a group of the general formula NR 4 R 5 or SO_ {NR} {4} R_ {5} or CONR_ {4} R_ {5} in which R_ {4} and R_ {5} each represent, independently of each other, a hydrogen atom or a group linear or branched (C 1 -C 6) alkyl or cycloalkyl (C 3 -C 7), or R 4 and R 5 form, with the nitrogen atom that carries them, a cycle pyrrolidine, piperidine or morpholine.

The compounds of formula (I) have two or three asymmetric centers depending on whether R2 is in position 2 or 3, 4, 5 and 6. They may exist, therefore, in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures, are part of the invention.

More particularly, the compounds of formula (I) may exist in the form of enantiomers or threo [(1 S , 2 S ) and (1 R , 2 R )] or erythro [(1 S , 2 R ) and (1) diastereoisomers R , 2 S )] with a stereochemistry of cis or trans piperidine substituents or in mixture of such isomers.

The compounds of formula (I) may exist in the state of bases or acid addition salts. Such salts of addition form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, but salts of other acids useful, for example, for purification or isolation of compounds of formula (I) are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates or solvates, namely in the form of associations or combinations with one or more water molecules or with a solvent Such hydrates and solvates are part also of the invention.

The compounds of the invention have a particular activity as specific inhibitors of Glycine transporters glyt1 and / or glyt2.

The compounds of general formula (I) in which R1 is different from a hydrogen atom can be prepared by a procedure illustrated by scheme I below.

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Scheme one

2

A coupling of a diamine of general formula (II), in which R1, R2 and X are as were defined above (with R1 different from an atom of hydrogen) with an activated acid or an acid chloride of the formula general (III) in which Y represents an activated OH group or an atom of chlorine and R 3 is as defined above, using methods known to the person skilled in the art.

The diamine of general formula (II) with R2 in position 3, 4, 5 or 6 can be prepared with a procedure illustrated with scheme 2 below.

According to a first route, the alpha lithiation of the piperidine of general formula (IV) is carried out, in which R 2 is as defined above and Boc represents a 1,1-dimethylethoxycarbonyl group, by the sec - butyllithium in the presence of TMEDA ( N, N, N ', N' -tetramethylethylene-diamine) in a solvent ether such as diethyl ether at -78 ° C, to react the lithioamine formed in situ on the benzaldehyde derivative of the formula general (VI), in which X is as defined above. Thus, a mixture of alcohol of general formula (VIII) and cyclic carbamate of general formula (IX) is obtained.

These compounds can also be obtained according to a second way as follows: either the aldehyde of general formula (V) according to the methods described in the bibliography, or is prepared from piperidine from general formula (IV) after lithiation and condensation on dimethyl formaldehyde under the conditions previously described. It is then reacted with the derivative of general formula (VII), in which X is as defined above and M represents a metal like lithium, in an ether solvent such as diethyl ether, between -30ºC and room temperature to obtain the compounds of general formulas (VIII) and (IX).

The alcohol of the general formula (VIII) of the threo / erythro configuration is transformed into the alcohol of the general formula (XI) of the threo configuration in two steps as follows: the alcohol is oxidized in ketone of the general formula (X) by an oxidant such as pyridinium chlorochromate in a chlorinated solvent such as dichloromethane at room temperature, and then the ketone is reduced in a diastereoselective manner in threo alcohol of general formula (XI) using a reducer such as K-Selectride® or L-Selectride® (tri- sec -butyl-potassium borohydride or lithium), in a solvent ether such as tetrahydrofuran, between -78 ° C and room temperature.

Then, the carbamate of the general formula (XI) of the threo configuration can be reduced to N -methylaminoalcohol threo of the general formula (XII) by the action of a mixed hydride such as the aluminum and lithium double hydride in a solvent ether such as tetrahydrofuran, between room temperature and reflux temperature.

Under the same reduction conditions, the cyclic threo carbamate of the general formula (IX) also leads to the N -methylaminoalcohol derivative threo of the general formula (XII).

The treo / erythro cyclic carbamate mixture of general formula (IX) leads to the mixture of threo / erythro derivatives of general formula (XII), which can be purified and separated by silica gel chromatography to obtain the treo compound Pure and the pure erythro compound.

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Scheme 2

3

Next, the threo alcohol of general formula (XII) in the intermediate broo of general formula (II) in which R1 represents a methyl group, in two stages: first, the alcohol function is transformed into a nucleophilic group, by an example, a methanesulfonate group, by the action of methylsulfonyl, in a chlorinated solvent such as dichloromethane, and in the presence of a base such as triethylamine, between 0 ° C and room temperature, and then the nucleophilic group is reacted with liquefied ammonia at -50 ° C, in an alcohol such as ethanol, in a half closed as an autoclave, between -50ºC and the temperature ambient.

Also, carbamate can be unprotected from general formula (XI) of threo configuration by means of a base strong as aqueous potash, in an alcohol like methanol to obtain the amino alcohol alcohol of general formula (XIII). In the same hydrolysis conditions, the cyclic carbamate of formula general (IX) leads to the amino alcohol of general formula (XIII).

Next, an N-alkylation is carried out by means of a halogenated derivative of formula R 1 Z, in which R 1 is as defined above, but different from a hydrogen atom, and Z represents a halogen atom, in the presence of a base such as potassium carbonate, in a polar solvent such as N, N- dimethylformamide, between room temperature and 100 ° C to generate an alkylated derivative of the general formula (XIV). Then, the alkylated derivative of the general formula (XIV) is transformed into the intermediate of the general formula (II) as described by way of the alcohol of the general formula (XII).

You can proceed in the same way as previously with the derivatives of general formula (IX) erythro for obtain the compounds of general formula (I) erythro.

The diamine of general formula (II) with R2 in position 2 it can be prepared with a procedure illustrated by Scheme 3 below.

Scheme 3

4

A piperidinone of formula is reacted general (XV), in which R_ {1} is as defined previously, with an organometallic of general formula (XVI), with reflux in tetrahydrofuran and the reaction mixture is treated with a solution of potassium cyanide to give rise to amino-nitrile of the general formula (XVII). TO the latter is then reacted with a lithiated derivative of general formula (VII), in which X is as defined above, in a solvent ether such as diethyl ether or tetrahydrofuran, between -90 ° C and -30 ° C; you get an imina intermediate of general formula (XVIII) which is reduced to amine primary treo of general formula (II) by means of a reducer such as sodium borohydride, in a protic solvent such as methanol, between 0 ° C and room temperature.

The compounds of general formula (I) in which R1 represents a hydrogen atom can be prepared at starting from a compound of general formula (I) in which R1 It represents:

-

good an optionally substituted phenylmethyl group, deprotecting the nitrogen from the piperidine cycle, for example, with an oxidant or with a Lewis acid such as boron tribromide, or by hydrogenolysis,

-

good an alkenyl group, preferably allyl, deprotecting the nitrogen from the piperidine cycle, for example, with a Pd ° complex to obtain a compound of general formula (I) in which R1 It represents a hydrogen atom.

The general formula piperidinone (XV) is commercially available

On the other hand, the chiral compounds of general formula (I) can be obtained by separation of racemic compounds by high-performance liquid chromatography resolution (HPLC) on a chiral column, or by splitting the racemic amine of general formula (II) with the use of a chiral acid, such as tartaric acid, acid Camforsulfonic acid, dibenzoyl-tartaric acid, N-acetyl-leucine, by fractional and preferential retro-crystallization of a salt diastereoisomeric in an alcoholic type solvent.

The piperidines of general formulas (IV) are prepared by protection, with a Boc group, for example, from the nitrogen of the corresponding piperidines, commercially available or described in the literature, according to the methods known to those skilled in the art. The method of forming lithiopiperidine from piperidine of the general formula (IV) and its reaction on the benzaldehyde of the general formula (VI) is analogous to that described in JO C. , 55 , (1990), 2578-2580. The phenyl-lithiated compound of the general formula (VII), in which X represents a hydrogen atom, is commercially available. Its substituted derivatives can be prepared according to a method analogous to that described in Tetrahedron Lett ., 57 , 33, (1996), 5905-5908. The aldehydes of the general formula (V) in which R 2 represents a methyl group at positions 2, 4, 5 and 6 are described in JO C. , 58 , (1993), 1109-117 and J. Chem. Soc., Perkin Trans. 1 , (2002), 1438-1443. Halogenated derivatives of formula R 1 Z are commercially available. Some acids and acid chlorides of the general formula (III) are commercially available or, when new, can be obtained by methods analogous to those described in European patents No. EP 0556672, of the USA. UU. No. 3801636 and in J. Chem. Soc ., (1927), 25, Chem. Pharm. Bull ., (1992), 1789-1792, Aust. J. Chem ., (1984), 1938-1950 and JO C. , (1980), 527.

The examples that will come later illustrate the Preparation of some compounds of the invention. Microanalysis  Elemental, IR and NMR spectra and chiral column HPLC confirm the enantiomeric structures and purities of the compounds obtained.

The numbers indicated in parentheses in the The titles of the examples correspond to those of the 1st column of the table offered below.

In the names of the compounds, the script "-" is part of the term, and the script "_" only serves to cut the words at the end of the line; must be removed in absence cutting and should not be replaced by a normal dash or by a space.

Example 1

(Compound No. one)

1- cis -treo-2-chloro- N - [(1,6-dimethyl-piperidin-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1 1.1. 1,1-dimethyl ethyl Cis [2-hydroxy (phenyl) methyl-6-methyl] piperidine-1-carboxylate

In a 50 ml flask, under a nitrogen atmosphere, 1 g (4.4 mmol) of 1,1-dimethyl ethyl cis 2-formyl-6-methylpiperidine-1-carboxylate is introduced into 15 ml of anhydrous tetrahydrofuran, the mixture is cooled to -78 ° C, 4.4 ml (4.4 mmol) of a 1M solution of phenylmagnesium bromide in the tetrahydrofuran is added dropwise and the mixture is allowed to return at -50 ° C by stirring for 2 h .

After hydrolysis with a solution aqueous saturated ammonium chloride, the aqueous phase is separated and extract with ethyl acetate. The combined organic phases are dried on sodium sulfate, filtered, concentrated under low pressure and purify the rest by silica column chromatography eluting with a mixture of ethyl acetate and cyclohexane.

1.15 g of alcohol are obtained in the form of a mixture of threo / erythro diastereoisomers.

1.2. Cis 2-methyl-6- (phenylcarbonyl) piperidine-1-carboxylate 1,1-dimethylethyl

In a 100 ml flask, 0.12 g (1.5 mmol) of sodium acetate suspended in 20 ml of dichloromethane and 1.2 g (5.5 mmol) of pyridinium chlorochromate are introduced successively and then a solution of 1.15 g (3.76 mmol) of 1,1-dimethylethyl cis [2-hydroxy (phenyl) methyl-6-methyl] piperidine-1-carboxylate in 20 ml of dichloromethane is added. The mixture turns black quickly and is left under stirring at room temperature for 4 h.

30 ml of ethyl ether are added, filtered, rinse, concentrate at low pressure and purify the rest by silica gel column chromatography eluting with a mixture of ethyl acetate and cyclohexane.

0.46 g of the ketone are obtained in the form of a white solid

Melting point: 92-93 ° C.

1.3 1,1-dimethylethyl Cis -treo- [2-hydroxy (phenyl) methyl-6-methyl] piperidine-1-carboxylate

In a 100 ml flask, under argon, 0.46 g (1.5 mmol) of 1,1-dimethylethyl cis 2-methyl-6- (phenylcarbonyl) piperidine-1-carboxylate are introduced into 40 ml of anhydrous tetrahydrofuran, the solution is cooled to -78 ° C, 4.6 ml (4.6 mmol) of a 1M solution of L-Selectride® (tri- sec -butylboroborohydride) in tetrahydrofuran is added dropwise , and the mixture is stirred at -78 ° C for 5 h.

It is cold hydrolyzed slowly with 3.2 ml of water and 3.2 ml of an aqueous solution with 35% peroxide of hydrogen, and the mixture is allowed to return to room temperature stirring it for 2 h.

It is diluted with water and ethyl acetate, The phases are separated and the aqueous phase is extracted with ethyl acetate. After washing the combined organic phases, drying on Sodium sulfate, from filtration and evaporation, is purified the residue by silica gel column chromatography eluting with a mixture of ethyl acetate and cyclohexane.

0.38 g of the threo cis isomer is obtained in the form of a colorless oil.

1.4. Cis -treo- (1,6-dimethylpiperidine-2-yl) phenylmethanol

In a 25 ml two-mouth flask, under nitrogen atmosphere, 0.24 g (6.3 mmol) of aluminum and lithium double hydride are introduced into 7 ml of anhydrous tetrahydrofuran, the mixture is heated with reflux, 1.38 g (1.2 mmol) of a solution of 1,1-dimethylethyl cis -treo- [2-hydroxy (phenyl) methyl-6-methyl] piperidine-1-carboxylate in 3 ml of tetrahydrofuran is added thereto and The mixture is refluxed for 3.5 h.

It is cooled, slowly hydrolyzed with a 0.1 M solution of double potassium and sodium tartrate, and leave Stir the mixture overnight.

Filter, rinse the precipitate with tetrahydrofuran, the filtrate is concentrated under low pressure and Purify the residue by gel column chromatography. silica eluting with a mixture of dichloromethane and methanol.

0.11 g of an oily product is obtained colorless.

1.5. Cis -treo- (1,6-dimethylpiperidinyl-2-yl) phenylmethanamine

In a 25 ml flask, under a nitrogen atmosphere, 0.11 g (0.52 mmol) of cis -treo- (1,6-dimethylpiperidin-2-yl) phenylmethanol and 0.11 ml (0.78) are introduced mmol) of triethylamine in 7 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C, 0.06 ml (0.78 mmol) of methanesulfonyl chloride is added, the mixture is allowed to slowly return to room temperature for 2 h and is concentrated at low pressure

In an autoclave provided with agitation magnetic and cooled to -50ºC, liquefied ammonia is introduced, it is add a solution of prepared crude methanesulfonate previously in a solution in 30 ml of absolute ethanol, Close the autoclave and stirring is maintained for 48 hours.

The mixture is transferred to a flask, concentrated drying it, the residue is diluted with water and dichloromethane, The phases are separated and the aqueous phase is extracted with dichloromethane. After washing the combined organic phases, drying on sodium sulfate, filtration and evaporation, it they isolate 0.1 g of amine in the form of an oily compound that use as is in the next stage.

1.6. 1- cis -treo-2-chloro- N - [(1,6-dimethyl-piperidin-2-yl) (phenyl) methyl] -3- (trifluoromethyl) -benzamide hydrochloride 1: 1

In a 25 ml flask, 0.13 g (0.58 mmol) of 2-chloro-3-trifluoromethanebenzoic acid, 0.11 g (0.59 mmol) of 1- [3- (dimethyl) hydrochloride are successively introduced -amino) propyl] -3-ethylcarbodiimide, 0.03 g (0.24 mmol) of dimethylaminopyrine in solution in 4 ml of dichloromethane and 0.10 g (0.48 mmol) of cis -treo- (1, 6-dimethylpipe-
Ridinyl-2-yl) phenylmethanamine in solution in 1 ml of dichloromethane and the mixture is left under stirring for 5 h.

It is treated with water and extracted several times with dichloromethane After washing the organic phases with water, and then with an aqueous solution of 1 N soda, drying on magnesium sulfate, filtration and evaporation of Low pressure solvent, the residue is purified by silica gel column chromatography eluting with a mixture of dichloromethane and methanol.

0.18 g of the oily product is obtained which is insulates in the form of hydrochloride from a 0.1 N solution of hydrochloric acid in propan-2-ol.

Finally, 0.12 g of hydrochloride is isolated in Shape of a white solid.

Melting point: 208-209 ° C.

Example 2

(Compound No. 9)

1- cis -treo-2-chloro- N - [(1,4-dimethyl-piperidinyl-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1 2.1 Cis -7-methyl-1-phenylhexahydro [1,3] oxazolo [3,4- a ] pyridin-3-one

In a 1L flask, under argon, 14.2 g (71.2 mmol) of 1,1-dimethyl ethyl 4-methylpiperidine-1-carboxylate in solution in 130 ml of anhydrous diethyl ether are introduced and the reaction at -70 ° C. 14 ml (92.5 mmol) of TMEDA ( N, N, N ', N' -tetra-methylethylene-diamine) are added and then 70 ml (92.5 mmol) of a 1.3 M solution of sec - butyl lithium in cyclohexane and allowed to return to -30 ° C with stirring for 0.5 hours.

Next, a solution of 11.33 ml (106.8 mmol) of benzaldehyde (previously distilled) in 40 ml of anhydrous diethyl ether and the mixture is allowed to return with stirring to room temperature for 12 h.

After hydrolysis with water, the aqueous phase and extracted with ethyl acetate. The phases are dried organic compounds on sodium sulfate, filtered, concentrated to low pressure and the residue is purified by chromatography on silica column eluting with a mixture of dichloromethane and methanol

3.3 g of colorless oil are obtained from a mixture of cis threo / erythro isomers.

2.2. Cis -treo- (1,4-dimethylpiperidin-2-yl) phenylmethanol

In a 500 ml two-mouth flask, under a nitrogen atmosphere, 2.71 g (71.5 mmol) of aluminum and lithium double hydride are introduced into 120 ml of anhydrous tetrahydrofuran, the mixture is heated with reflux, add 3.33 g (14.3 mmol) of a solution of cis -7-methyl-1-phenylhexahydro- [1,3] oxazolo [3,4- a ] pyridin-3-one in 40 ml of tetrahydrofuran and keep the mixture with reflux for 5.5 h.

It is cooled, slowly hydrolyzed with a 0.1 M solution of double potassium and sodium tartrate, and leave Stir the mixture overnight.

Filter, rinse the precipitate with tetrahydrofuran, the filtrate is concentrated under low pressure and Purify the residue by gel column chromatography of silica eluting with a mixture of dichloromethane and methanol.

0.95 g of a product are obtained in the form of colorless oil

2.3. Cis -treo- (1,4-dimethylpiperidinyl-2-yl) phenylmethanamine

In a 10 ml flask, under nitrogen atmosphere, 0.95 g (4.3 mmol) of cis -treo- (1,4-dimethylpiperidin-2-yl) phenylmethanol and 0.9 ml (6.5) are introduced mmol) of triethylamine in 40 ml of anhydrous dichloromethane, the medium is cooled to 0 ° C, 0.5 ml (6.5 mmol) of methanesulfonyl chloride is added, the mixture is allowed to slowly return to room temperature for 2 h and is concentrated to low pressure.

In an autoclave provided with agitation magnetic and cooled to -50 ° C, liquefied ammonia is introduced, add a solution of prepared crude methanesulfonate previously in solution in 30 ml of absolute ethanol, it is closed the autoclave and stirring is maintained for 48 h.

The mixture is transferred to a flask, concentrated drying it, the residue is diluted with water and dichloromethane, The phases are separated and the aqueous phase is extracted with dichloromethane. After washing the combined organic phases, drying on sodium sulfate, filtration and evaporation, it they isolate 0.8 g of the amine in the form of an oily compound that use as is in the next stage.

2.4. 1- cis -treo-2-chloro- N - [(1,4-dimethyl-piperidin-2-yl) (phenyl) methyl] -3- (trifluoromethyl) -benzamide hydrochloride 1: 1

In a 50 ml flask, 0.98 g (4.38 mmol) of 2-chloro-3-trifluoromethanebenzoic acid, 0.85 g 4.46 mmol) of 1- [3- (dimethyl-) hydrochloride are successively introduced amino) propyl] -3-ethylcarbodiimide, 0.22 g (1.83 mmol) of dimethylaminopyrine in solution in 20 ml of dichloromethane and 0.8 g (3.66 mmol) of cis -treo- (1, 4-dimethylpiperidin-2-yl) phenylmethanamine in solution in 4 ml of dichloromethane, and the mixture is left under stirring for 12 h.

It is treated with water and extracted several times with dichloromethane After washing the organic phases with water, and then with an aqueous solution of 1 N soda, drying on magnesium sulfate, filtration and evaporation of Low pressure solvent, the residue is purified by silica gel column chromatography eluting with a mixture of dichloromethane and methanol.

0.32 g of the oily product is obtained which is insulates in the form of hydrochloride from a 0.1 N solution of hydrochloric acid in propan-2-ol.

Finally, 0.28 g of hydrochloride is isolated in Shape of a white solid.

Melting point: 209-211 ° C.

Example 3

(Compound No. 5)

Trans -treo-2-chloro- N - [(1,5-dimethyl-piperidinyl-2-yl) (4-fluorophenyl-methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1.

Proceeding in the same manner as in Example 2 and replacing 1,1-dimethyl ethyl 4-methylpiperidine-1-carboxylate with 1,1-dimethyl ethyl 5-methylpiperidine-1-carboxylate and benzaldehyde with 4-fluorobenzaldehyde, obtains a mixture of the corresponding alcohol and isoxazolidone. The reduction of the isoxazolidone obtained by the double aluminum and lithium hydride gives the treo trans aminoalcoholic compound which is used according to the methods described in steps 2.3 and 2.4 of example 2 with 2-chloro-3-trifluoromethanebenzoic acid.

Melting point: 220-222 ° C.

Example 4

(Compound No. 10)

1- cis -treo 2-chloro- N - [(1,2-dimethylpiperidin-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1 4.1. 1,2-dimethylpiperidine-2-carbonitrile

In a 500 ml three-mouth flask equipped with a refrigerant and with magnetic stirring, they are introduced, in nitrogen atmosphere, 22 ml (31 mmol) of a bromide solution of methylmagnesium at 1.4 M in tetrahydrofuran and then a solution 5 g (44.2 mmol) of 1-methylpiperidin-2-one in 20 ml of tetrahydrofuran, and the mixture is heated under stirring at reflux for 2 h.

The mixture is allowed to cool, 50 ml of a 2 N solution of hydrochloric acid and extracted with acetate ethyl. Then, the aqueous phase is adjusted to pH 6 with the help of baking soda and 2.9 g (2.8 mmol) of cyanide are added potassium. Then, it is left under stirring at 25 ° C for 12 h.

A 10% solution of bicarbonate is added of sodium and extracted with ethyl acetate. After washing the combined organic phases, of drying over sodium sulfate, of filtration and evaporation, 3 g of product are obtained in form of an oily compound that is used as is in the stage next.

4.2. 1- (1,2-dimethylpiperidin-2-yl) -1-phenylmethanamine

In a 250 ml flask equipped with shaking magnetic and in an argon atmosphere, it is prepared at -78 ° C phenyl lithium solution from 6.8 g (43.4 mmol) of bromobenzene in 50 ml of tetrahydrofuran and 17.4 ml of butyl lithium (2.5 M in hexane). It is introduced, at 78 ° C, a solution of 3 g (21.71 mmol) of 1,2-dimethyl-piperidine-2-carbonitrile  in 50 ml of tetrahydrofuran and it is left under stirring that the mixture (yellowish solution) return to room temperature for 1 h. Water is added and extracted with ethyl acetate. The ones are dried organic phases combined on sodium sulfate, filtered and Concentrate the imine at low pressure.

The rest is recovered in a 250 ml flask with 50 ml of methanol The mixture is cooled to 0 ° C and slowly added 4 g (108 mmol) of sodium borohydride. Stirring continues letting the temperature of the mixture return to the temperature ambient for 1 h. The mixture is concentrated under low pressure and Recover with water and ethyl acetate. The phases are separated and Extract the aqueous phase with ethyl acetate. After washing the combined organic phases, of drying over sodium sulfate, of filtration and evaporation, 3.2 g of product are obtained in form of an oily compound that is used as is in the stage next.

4.3 2-Chloro- N - [(1,2-dimethylpiperidin-2-yl) (phenyl) methyl] -3- (trifluoromethyl) benzamide hydrochloride 1: 1

In a 100 ml flask, they are introduced successively, in 20 ml of dichloromethane, 0.41 g (1.8 mmol) of 1- (1,2-dimethylpiperidin-2-yl) -1-phenylmethanamine,  0.3 ml (2.25 mmol) of triethylamine, 0.54 g (2.25 mmol) of chloride of acid 2-Chloro-3- (trifluoromethyl) benzoic  and the mixture is stirred at room temperature for 1 h.

It is treated with water and extracted several times with dichloromethane After washing the organic phases with water, and then with an aqueous solution of 1 N soda, drying on magnesium sulfate, filtration and evaporation of Low pressure solvent, the residue is purified by silica gel column chromatography eluting with a mixture of dichloromethane and methanol.

0.36 g of oily product are obtained.

It is transformed into hydrochloride from a 0.1 N solution of hydrochloric acid in propan-2-ol.

Finally, 0.14 g of hydrochloride is isolated in Shape of a white solid.

Melting point: 239-241 ° C.

The following table illustrates the structures chemical and physical properties of some compounds of the invention.

In the "salt" column, "HCl" designates a hydrochloride

5

6

The compounds of the invention have been subjected to a series of pharmacological trials that have revealed its interest as substances with therapeutic activities.

Study of glycine transport in cells SK-N-MC expressing the native glyt1 human transporter

[14 C] glycine intake is studied in SK-N-MC cells (cells human neuro-epithelial) that express the native glyt1 human transporter by measuring the radioactivity incorporated in the presence or absence of the compound Approve. The cells are cultured in monolayer for 48 hours in plates pretreated with 0.02% fibronectin. The day of experiment, the culture medium is removed and the cells are washed using a Krebs-HEPES buffer (acid [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid) at pH 7.4. After 10 min of preincubation at 37 ° C in the presence either of a buffer (control lot), or of the compound to be tested in different concentrations or 10 mM glycine (determination of unspecific taking), then 10 µM of [14 C] glycine (specific activity 112 mCi / mmol). Be incubation continues for 10 min at 37 ° C and the reaction by 2 washes with a buffer Krebs-HEPES at pH 7.4. Then, the radioactivity incorporated by cells after adding 100 µl of scintillation liquid and stir for 1 h. The count is performed on a Tri-lux ™ Microbeta counter. The effectiveness of the compound is determined by the IC50, concentration of the compound that decreases the specific intake by 50% of glycine, defined by the difference in radioactivity incorporated by the control lot and the lot that has received the glycine  at 10 mM.

The most active compounds of the invention, in This test has an IC 50 of the order of 0.001 to 10 µM.

The individual results of some Compounds are as follows (IC 50 in µM):

Compound No. 1

0.51

Compound No. 5

0.1

Compound No. 19

0.09

Compound No. 10

0.008

Ex vivo study of the inhibitory activity of a compound on the intake of [14 C] glycine in mouse cortical homogenate

Increasing doses of the compound to be studied are administered orally (preparation by crushing the molecule to be tested in a mortar in a solution of Tween / Methocel ™ at 0.5% in distilled water) or intraperitoneal (dissolution of the molecule to be tested in physiological serum or preparation by crushing in a mortar in a solution of 0.5% Tween / Methocel in water, depending on the solubility of the molecule) in male mice OF1 Iffa Crédo from 20 to 25 g on the day of experiment. The witness group is treated with the vehicle. The dose  in mg / kg, the route of administration and the treatment time are determine depending on the molecule to study.

After the painless sacrifice by decapitation of animals at a certain time after administration, the bark of each animal is quickly taken in ice is weighed and preserved at 4 ° C or frozen at -80 ° C (in both cases, the samples are kept for a maximum of 1 day). Each sample is homogenize in a Krebs-HEPES buffer at pH 7.4 a 10 ml / g ratio of tissue. 20 µl of each are incubated homogenized for 10 min at room temperature in the presence of 10 mM L-alanine and buffer. The shot is determined nonspecific by adding 10 mM glycine to the control group. Be the reaction is stopped by vacuum filtration and the radioactivity retained by scintillation by counting on a Tri-lux ™ Microbeta counter.

An inhibitor of taking [14 C] glycine will decrease the amount of radioligand that It is incorporated into each homogenate. The activity of the composed by means of its DE 50, a dose that inhibits 50% of the intake of [14 C] glycine with respect to the control group.

The most potent compounds of the invention, in This test has an ED 50 of 0.1 to 5 mg / kg per route intraperitoneal or orally.

Study of the transport of glycine in the homogenate of mouse spinal cord

The taking of the [14 C] glycine by the glyt2 transporter in the homogenized mouse spinal cord by measuring the radioactivity incorporated in the presence or absence of the compound a study.

After the painless sacrifice of animals (male mice OF1 Iffa Crédo weighing 20 to 25 g on the day of experiment), the spinal cord of each animal is quickly taken, It is weighed and preserved on ice. The samples are homogenized in a Krebs-HEPES buffer (acid [4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid),  pH 7.4, at a rate of 25 ml / g of tissue.

50 µl of the homogenate are pre-incubated for 10 min at 25 ° C in the presence of the buffer Krebs-HEPES, pH 7.4 and the compound to be studied in different concentrations, or 10 mM glycine to determine the takes nonspecific Then the [14 C] glycine (specific activity = 112 mCi / mmol) for 10 min at 25 ° C at the final concentration of 10 µM. Be the reaction is stopped by vacuum filtration and the radioactivity by solid scintillation by counting in a counter Tri-lux ™ microbeta.

The efficacy of the compound is determined by the IC 50 capable of reducing the specific glycine intake by 50%, defined by the difference in radioactivity incorporated by the control lot and the lot that has received the glycine at
10 mM

The most active compounds of the invention, in This test has an IC 50 of the order of 0.001 to 10 µM.

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The individual results of some Compounds are as follows (IC 50 in µM):

Compound No. 1

0.12

Compound No. 9

0.07

Ex vivo study of the inhibitory activity of a compound on the intake of [14 C] glycine in mouse spinal homogenate

Increasing doses of the compound to be studied are administered orally (preparation by crushing the compound to be tested in a mortar, in a Tween / Methocel ™ solution 0.5% in distilled water) or intraperitoneally (compound a try dissolved in physiological serum, or crushed in a mortar, in a 0.5% solution of Tween / Methocel ™ in distilled water) in mice the male OF1 Iffa Crédo from 20 to 25 g on the day of experiment. The witness group is treated with the vehicle. The dose in mg / kg, the route of administration, the treatment time as well how the time of painless sacrifice is determined based on compound to study.

After the painless sacrifice through the decapitation of animals at a certain time after administration, marrow is taken quickly, weighed and introduced into glass scintillation jars, preserved on ice crushed or frozen at -80 ° C (in both cases, the samples 1 day maximum). Each sample is homogenized in a Krebs-HEPES buffer at pH 7.4, at a rate of 25 ml / g of tissue. 50 µl of each homogenate are incubated for 10 min at room temperature in the presence of the buffer.

The unspecific take is determined by adding 10 mM glycine to the control group.

The reaction is stopped by filtration with vacuum and radioactivity is estimated by scintillation by microbeta counter count Tri-lux ™.

An inhibitor of taking [14 C] glycine will decrease the amount of radioligand that It is incorporated into each homogenate. The activity of the compound by means of its DE 50, an effective dose that inhibits 50% of taking [14 C] glycine with respect to the group of witness.

The most active compounds of the invention, in this test, have an ED 50 of 1 to 20 mg / kg per route intraperitoneal or orally.

The results of the tests carried out on the compounds of the invention show that they are inhibitors of glyt1 glycine transporters present in the brain and the glyt2 glycine present in the brain or spinal cord.

Therefore, the compounds according to the invention can be used to prepare medications, in particular, glyt1 glycine transporter inhibitor medications and / or glyt2.

Thus, according to another of its aspects, the invention is refers to medicaments comprising a compound of formula (I) or a salt of addition of the latter to a pharmaceutically acidic acceptable, or even a hydrate or solvate of the compound of formula (I).

The compounds of the invention can be use particularly in associated behavioral disorders with dementia, psychosis, particularly schizophrenia (form deficit and productive form) and in extrapyramidal symptoms acute or chronic neuroleptic-induced, for the treatment of various forms of anxiety, attacks of panic, phobias, obsessive compulsive disorders, for the treatment of different forms of depression, including psychotic depression, for the treatment of disorders due to alcohol abuse or withdrawal, from disorders of sexual behavior, of eating disorders food and for the treatment of migraine.

On the other hand, the compounds of the invention are can use for the treatment of muscle contractures painful in rheumatology and acute spinal disease, for treatment of spastic contractures of spinal origin or cerebral, for the symptomatic treatment of acute pain and subacute of light to moderate intensity, for the treatment of severe and / or chronic pain, neurogenic pain and rebel pains, for the treatment of Parkinson's disease and of parkinsonian symptoms of neurodegenerative origin or induced by neuroleptics, for the treatment of generalized primary and secondary epilepsy, partial with simple or complex symptomatology, of mixed and other forms epileptic disorders as a complement to another treatment antiepileptic, or monotherapy, for the treatment of barely of sleep and for neuroprotection.

The present invention also aims at pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the state of base or of pharmaceutically acceptable salt or solvate, and in mixture, if it is necessary, with one or more suitable excipients. Sayings excipients are chosen according to the pharmaceutical form and the mode of desired administration.

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Therefore, pharmaceutical compositions according to the invention can also be directed to the administration oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular.

Unit forms of administration may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal seals ("patch"), suppositories. For the topical administration, ointments, lotions and eye drops

As an example, a unitary form of administration of a compound according to the invention in the form of tablet can comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Cornstarch 15.0 mg hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg

These unit forms are dosed to allow a daily administration of 0.01 to 20 mg of principle active per kg of body weight, according to the galenic form.

There may be particular cases in which they are appropriate higher or lower doses; such doses are not out of the scope of the invention. According to usual practice, the Appropriate dosage for each patient is determined by the doctor according to the mode of administration, weight and response of said patient.

The present invention, according to another of its aspects, also refers to the use of a compound according to the invention for the preparation of a medicament intended for treatment of the diseases indicated above, said treatment comprising the administration, to a patient, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or hydrates or solvates.

Claims (9)

1. Compound that responds to the formula general (I) 7 in the that: R1 represents either a hydrogen atom, or a (C 1 -C 7) alkyl group linear or branched optionally substituted with one or more fluorine atoms, or a group cycloalkyl (C 3 -C 7), or a group (C 3 -C 7) cycloalkyl-(C 1 -C 3) alkyl, or a group phenyl (C 1 -C 3) alkyl  optionally substituted with one or two methoxy groups, or a alkenyl group (C2-C4), or a (C 2 -C 4) alkynyl group; R2 represents either a group linear or branched (C 1 -C 7) alkyl or cycloalkyl (C 3 -C 7), or a group (C 3 -C 7) cycloalkyl-(C 1 -C 3) alkyl; X represents either a hydrogen atom, or either one or several substituents chosen among the atoms of halogen and trifluoromethyl groups, linear or branched (C 1 -C 6) alkyl or (C 1 -C 6) alkoxy; R 3 represents either a hydrogen atom, or one or more substituents chosen among the atoms of halogen and trifluoromethyl groups, linear or branched (C 1 -C 6) alkyl, cycloalkyl (C 3 -C 7), (C 1 -C 6) alkoxy, phenyl, cyano, acetyl, benzoyl, thioalkyl (C 1 -C 6), (C 1 -C 6) alkyl sulfonyl, carboxy or (C 1 -C 6) alkoxy carbonyl, or either a group of the general formula NR 4 R 5 or SO_ {NR} {4} R_ {5} or CONR_ {4} R_ {5} in which R_ {4} and R_ {5} each represent, independently of each other, a hydrogen atom or a group linear or branched (C 1 -C 6) alkyl or cycloalkyl (C 3 -C 7), or R 4 and R 5 form, with the nitrogen atom that carries them, a cycle pyrrolidine, piperidine or morpholine; in the free base state or salt of addition to an acid, hydrate or solvate. 2. Compound according to claim 1, characterized in that it is of a threo configuration; in the state of free base or salt of addition to an acid, hydrate or solvate. 3. Compound according to claim 2, characterized in that it is of configuration (1 S , 2 S ) or (1 R , 2 R ); in the state of free base or salt of addition to an acid, hydrate or solvate. 4. Compound according to claim 1, characterized in that it is of erythro configuration; in the state of free base or salt of addition to an acid, hydrate or solvate. 5. Compound according to claim 4, characterized in that it is of configuration (1 S , 2 R ) or (1 R , 2 S ); in the state of free base or salt of addition to an acid, hydrate or solvate. 6. A medicament, characterized in that it comprises a compound according to any one of claims 1 to 5, or an addition salt of this compound to a pharmaceutically acceptable acid, or even a hydrate or a solvate of the compound of formula (I). 7. Pharmaceutical composition, characterized in that it comprises a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, a hydrate or a solvate of this compound, as well as at least one pharmaceutically acceptable excipient. 8. Use of a compound of formula (I) according to one of claims 1 to 5 for preparing a medicament  intended for the treatment of behavioral disorders associated with dementia, psychosis, in various ways of anxiety, of panic attacks, of phobias, of obsessive compulsive disorders, of the different forms of depression, of disorders due to abuse or withdrawal from alcohol, of sexual behavior disorders, of disorders of food intake and migraine.

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9. Use of a compound of formula (I) according to one of claims 1 to 5 for preparing a medicament  intended for the treatment of contractures, pain, Parkinson's disease and parkinsonian symptoms of epilepsy, mixed forms and other epileptic disorders as a complement to another antiepileptic treatment, or in monotherapy, sleep apnea and neuroprotection.